[ CAS No. 1001020-08-1 ]

Name: 1001020-08-1|tert-Butyl 2-amino-3-carbamoyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate|98%
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Quality Control of [ 1001020-08-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1001020-08-1 ]

SDS Specification

Alternatived Products of [ 1001020-08-1 ]

Product Details of [ 1001020-08-1 ]

CAS No. :	1001020-08-1	MDL No. :	MFCD11108853
Formula :	C₁₃H₁₉N₃O₃S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RITBMKDFXNCZCM-UHFFFAOYSA-N
M.W :	297.37	Pubchem ID :	50873949
Synonyms :

Calculated chemistry of [ 1001020-08-1 ]

Physicochemical Properties

Num. heavy atoms :	20
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.54
Num. rotatable bonds :	4
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	82.0
TPSA :	126.89 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.09 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.4
Log Po/w (XLOGP3) :	1.44
Log Po/w (WLOGP) :	1.2
Log Po/w (MLOGP) :	0.67
Log Po/w (SILICOS-IT) :	1.57
Consensus Log Po/w :	1.46

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.51
Solubility :	0.915 mg/ml ; 0.00308 mol/l
Class :	Soluble
Log S (Ali) :	-3.71
Solubility :	0.058 mg/ml ; 0.000195 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.95
Solubility :	3.31 mg/ml ; 0.0111 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	1.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.04

Safety of [ 1001020-08-1 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P280-P305+P351+P338	UN#:
Hazard Statements:	H302	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 1001020-08-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 1001020-08-1 ]

[ 1001020-08-1 ] Synthesis Path-Downstream 1~69

1
[ 79099-07-3 ]
[ 107-91-5 ]
[ 1001020-08-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With morpholine; sulfur; In ethanol; at 20℃;	A round bottom flask fitted with a stir bar, was charged with sulfur (196 mg, 6.114 mmol) followed by morpholine (704 pL, 8.14 mmol) and the suspension was stirred at 40 C for 1 h or until sulfur dissolved in morpholine. The solution was diluted with anhydrous ethanol (EtOH), whereupon 4-N-Boc-piperidinone (1.20 g, 6.02 mmol) and cyanamide (506 mg, 6.02 mmol) were added and the reaction mixture stirred at room temperature overnight. Upon completion, the reaction mixture was concentrated in vacuo to afford viscous orange oil. The resultant product was diluted with methanol (MeOH) and then 10% ethyl acetate (EtOAc) in Hexane was added until precipitation of the product was complete. The product was filtered to afford tan solid (1.8 g, quantitative yield). 1H NMR (300 MHz, MeOH-i) d 4.35 (bs, 2H), 3.68-3.55 (m, 2H), 2.71-2.68 (m, 2H), 1.49 (s, 9H). LRMS [M+H] 298.
93%	With sulfur; diethylamine; In ethanol; at 20℃;	Synthesis of 2-Amino-3-carbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyridine-6- carboxylic acid tert-butyl ester (3)Starting material 1 (25 g, 125 mmol) was suspended in a 250 ml bowl flask in 125 ml abs. ethanol and mixed with starting material 2 (10.5 g, 125 mmol) and sulfur (4.023 g, 125 mmol). 12.9 ml (125 mmol) diethyl amine was added dropwise to the yellow suspension, which thereby became of orange color. The reaction mixture was stirred over night at ambient temperature. Next day, the reddish solution was concentrated in vacuo and the crude product was re-crystallized in methanol. The desired product 3 was isolated as a red-brown solid (40.7 g, 116 mmol, 93%).
83%	With morpholine; sulfur; In ethanol; for 8h;Reflux;	Preparation of intermediate I, tert-butyl 4-oxopiperidine-1-carboxylate (30.0 mmol), 2-cyanoacetamide (30.0 mmol) and sulfur (30.0 mmol)Morpholine (30.0 mmol) was added to the absolute ethanol (200 mL) solution. The resultant was refluxed for 8 hours.The suspension was cooled to ambient temperature, and filtered through a pad of diatomaceous earth, and washed with absolute ethanol (30 mL × 3). The combined filtrate was concentrated to dryness. The crude product was diluted with 95% ethanol (30 mL) and filtered to obtain a white solid product as shown in Formula I with a yield of 83%.

82%	With morpholine; sulfur; In ethanol; at 20℃; for 12h;	To the stirred solution of compound 2 (6.0 g, 30.14 mmol), cyanoacetamide (3.01 g, 37.18 mmol), sulphur powder (2.13 g,30.14 mmol) in ethanol (60 mL) was added morpholine (6.01 mL,60.30 mmol) and stirred the reaction mixture at room temperaturefor 12 h the reaction mixture was concentrated, and the crude solid was filtered, washed with H2O and dried in vacuum oven for 2 h.The obtained dried compound was purified by column chromatography to yield (3.67 g, 82%) as a light yellow solid.
82%	With morpholine; sulfur; In ethanol; at 20℃; for 9h;	To the stirred solution of compound II (3.0 g, 15.07 mmol), 2-cyanoacetamide (1.51 g, 18.09 mmol), sulfur powder (1.06 g, 15.07 mmol) in ethanol (40 mL) was added morpholine (3.21 mL, 33.15 mmol) and stirred the reaction mixture at room temperature for 9 h. the reaction mixture was concentrated, diluted with EtOAc and washed the organic layer with H2O (2 * 30 mL). The separated organic layer was dried over anhydrous Na2SO4, evaporated and purified by column chromatography to get compound 4 (3.67 g, 82%) as an light yellow solid. ESI-MS found 298 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.25 (s, 2H), 7.90 (s, 2H), 4.32 (s, 2H), 3.51 (t, J = 6.8 Hz, 2H), 3.04 (t, J = 6.8 Hz, 2H).
82%	With morpholine; sulfur; In ethanol; at 20℃; for 9h;	To the stirred solution of Compound 5 (3.0 g, 15.07 mmol), 2-cyanoacetamide (1.51 g, 18.09 mmol), sulphur powder (1.06 g, 15.07 mmol) in Ethanol (40 mL) was added morpholine (3.21 mL, 33.15 mmol) and stirred the reaction mixture at room temperature for 9 h the reaction mixture was concentrated, diluted with EtOAc and washed the organic layer with H2O (3×40mL). The separated organic layer was dried over anhydrous Na2SO4, evaporated and purified by column chromatography to get Compound 6 (3.67 g, 82%) as a light yellow solid. ESI-MS found 298 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.25 (s, 2H), 7.90 (s, 2H), 4.32 (s, 2H), 3.51 (t, J=6.8Hz, 2H), 3.04 (t, J=6.8Hz, 2H).
81%	With sulfur; diethylamine; In ethanol; at 20℃;	Example 462-(2-(3-(trifluoromethyl)-4,516,7-tetrahvdroindazole-1-yl)acetamido -4.5.6.7-tetrahvdro thienof2,3-cipyridine-3-carboxamidea) terf-butyl 2-amino-3-carbamoyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylatetert-butyl 4-oxopiperidine-1-carboxylate (9.95 g, 50 mmol), cyanoacetamide (4.24 g, 50 mmol) and sulfur (1.6 g, 50 mmol) were stirred in EtOH (20 mL). Diethylamine (5 ml_, 48 mmol) was added and the reaction stirred at RT overnight. A gum had formed in the solution. Water (50 mL) was added and the solid filtered, washing with heptane (150 mL) to give a brown/yellow solid (12.0 g, 40 mmol, 81 %). MS (ESI) : m/z 298 [M + H]+.
81%	With sulfur; In ethanol; diethylamine; at 20℃; for 18h;	To prepare Intermediate 1, add N-Boc-4-piperidone (19.5 mmol) and elemental S (19.5 mol) to absolute ethanol (50 mL), add cyanoacetamide (19.5 mmol) to the mixture, and then slowly Add diethylamine (2.5 mL). The reactants were stirred at room temperature for 18 hours, the solvent was evaporated under reduced pressure, and the residue obtained was purified by silica gel chromatography using dichloromethane/methanol=(10:1) as the eluent for column chromatography to obtain a white solid intermediate 1. The yield was 81%.
78%	With morpholine; sulfur; In ethanol;Reflux;	Add tert-butyl 4-oxpiperidine-1-carboxylate (30.0mmol) in absolute ethanol (200ml),2-cyanoacetamide (30.0 mmol), sulfur (30.0 mmol), and then morpholine (30.0 mmol).After refluxing for 8 hours, the reaction solution was cooled to room temperature, filtered, washed with 30ml x 3 absolute ethanol, and the solvent was removed under reduced pressure.The crude product was crystallized from 95% ethanol (30 ml) to obtain a white solid with a yield of 78%.

Reference： [1]Patent: WO2020/33322,2020,A1 .Location in patent: Page/Page column 33; 34
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 84 - 97
[3]Patent: WO2010/112124,2010,A1 .Location in patent: Page/Page column 61-62
[4]Patent: CN110922415,2020,A .Location in patent: Paragraph 0012; 0013
[5]Journal of Medicinal Chemistry,2020,vol. 63,p. 3976 - 3995
[6]European Journal of Medicinal Chemistry,2014,vol. 76,p. 110 - 117
[7]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 1938 - 1947
[8]European Journal of Medicinal Chemistry,2015,vol. 92,p. 401 - 414
[9]Journal of Medicinal Chemistry,2020,vol. 63,p. 3678 - 3700
[10]Patent: WO2008/3452,2008,A1 .Location in patent: Page/Page column 44
[11]Patent: CN111662305,2020,A .Location in patent: Paragraph 0013; 0017
[12]Patent: CN111454278,2020,A .Location in patent: Paragraph 0033-0035; 0036; 0039; 0040
[13]Journal of Enzyme Inhibition and Medicinal Chemistry,2020,vol. 35,p. 1524 - 1538

2
[ 1001020-03-6 ]
[ 1001020-08-1 ]
[ 1001020-09-2 ]

Yield	Reaction Conditions	Operation in experiment
53%	With polymer supported carbonyldiimidazole; In dichloromethane; N,N-dimethyl-formamide; at 120℃; for 0.166667h;Microwave irradiation;	b) tert-butyl 3-carbamoyl-2-(2-(3-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-1- yl)acetamido -4,5-dihydrothieno[2,3-c]pyridine-6(7/-/)-carboxylatete/t-butyl 2-amino-3-carbamoyl-4,5-dihydrothieno[2,3-c]pyridine-6(7/-/)-carboxylate (72 mg, 0.24 mmol) and 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-7H-indazole-1-yl)acetic acid (60 mg, 0.24 mmol) were dissolved in DCM /DMF (3 mL/ 50 μl_) and polymer supported carbonyldiimidazole (396 mg, 1.2 mmol/g, 0.475 mmol) added. The reaction mixture was heated at 120 0C for 10 min in the microwave. The reaction mixture was filtered washing with MeOH (10 mL), EtOAc (10 mL), and MeCN (10 mL). The filtrate was concentrated in vacuo to give product as a yellow gum (67 mg, 0.0127 mmol, 53 %). MS (ESI) : m/z 528 [M + H]+.

Reference： [1]Patent: WO2008/3452,2008,A1 .Location in patent: Page/Page column 45

3
[ 1001020-08-1 ]
[ 104-12-1 ]
[ 1246966-73-3 ]

Yield	Reaction Conditions	Operation in experiment
57%	With triethylamine; In tetrahydrofuran; at 20℃; for 8h;	To a stirred solution of 4-chlorophenyl isocyanate (325 mg, 2.12 mmol) and triethylamine (444 pL, 3.18 mmol) in anhydrous tetrahydrofuran (THF) (10 mL) was added /er/-butyl 2-amino-3-carbamoyl-4,5-dihydrothieno[2,3-c]pyridine-6(7f/)- carboxylate (632 mg, 2.12 mmol) and the reaction mixture was stirred at room temperature (rt) for 8 h. The reaction mixture was concentrated in vacuo to afford oil, which was taken up dichloromethane (DCM) and washed with water (x2). The organics were then dried with anhydrous Na2S04and concentrated in vacuo. The product was purified by Isolera system (Si02gel as stationary phase, 25 g HP column, dry loading) using DCM-DCM/MeOH (0%- 8% MeOH in DCM) to afford tan solid (633 mg, 57% yield). LRMS [M+H] 451.
	In pyridine; at 20℃;	Synthesis of S-Carbamoyl^-β-^-chloro-phenyO-ureidoHy-dihydro-SH- thieno^.S-clpyridine-e-carboxylic acid tert-butyl ester (4)Compound 3 (1.5 g, 4.3 mmol) and p-Chlorphenylisocyanat (724 mg, 4.7 mmol) were dissolved in pyridine (12 ml) and stirred over night at room temperature. Another equivalent of isocyanate (724mg, 4.7 mmol) was added and the mixture was stirred over the weekend. The solvent was reduced under vacuum and the crude product (2.3 g, 4 mmol; light brown solid) was used in the next reaction without further purification (Content: 79% compound 4 according to UV).

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 84 - 97
[2]Patent: WO2020/33322,2020,A1 .Location in patent: Page/Page column 33; 34
[3]Patent: WO2010/112124,2010,A1 .Location in patent: Page/Page column 62

4
[ 194240-75-0 ]
[ 1001020-08-1 ]
[ 1246966-79-9 ]